The human and financial cost to our society for disorders such as substance abuse and psychopathology is staggering. One pathway by which these deleterious psychosocial sequelae may be expressed is through disrupted regulatory systems. However, little is known about the physiological underpinnings of this dysregulation. Cocaine might disrupt the neural systems that regulate arousal and attention, thereby impacting physiological markers of emotion regulation. Vagal Tone (VT) is a well-documented physiological marker of the organisms' ability to self-regulate. Thus, one of the broad goals of this research is to examine whether Prenatal Cocaine Exposure (PCE) impacts baseline VT and VT reactivity to cognitive challenge. We also know that children with (PCE) grow up in contexts of significant early life stress and environmental risk. We will therefore include measures of environmental risk to determine if PCE is a significant contributor to or simply a marker for adverse outcome. Another broad goal of the proposed research is to study pathways from prenatal cocaine exposure to neurobehavioral disinhibition in adolescence, a construct that is related to substance use and psychopathology. We ultimately plan to identify developmental pathways by which some children with PCE develop psychopathology and use illicit substances. Data come from the Maternal Lifestyle Study (MLS), the largest longitudinal birth cohort study of children with PCE. The proposed study includes approximately 1,000 subjects with and without PCE who have been followed since birth in the multisite MLS. Baseline VT and VT response to cognitive challenge was measured at 1, 4, 12, and 18 months and at years 2-7, 11, and 15. Across childhood and adolescence measures of psychopathology and substance use were administered. The specific aims are to: a) use Latent Growth Curve Modeling (LGCM) to examine trajectories of VT from infancy to adolescence in a sample of children with and without PCE; b) investigate indices of environmental risk as predictors of growth trajectories in VT to account for individual differences in children's physiological trajectories; and c) use Structural Equation Modeling to test a developmental model relating VT to neurobehavioral disinhibition among children with and without PCE. The proposed study will have a high impact because it places our understanding of PCE, and by implication other substances, in the broader perspective of research on prenatal stress from a developmental perspective that includes the effects of postnatal environmental adversity. This study directly addresses the NIDA 2010 strategic goal to prevent the initiation of drug use by understanding how biology and development influence the risk and predictive factors for drug abuse.